MOLECULAR GENETICS OF GYNECOLOGIC CANCERS

The thesis is focused on the molecular genetics of gynecologic cancers, specifically uterine serous carcinoma (USC) and ovarian clear cell carcinoma (OCCC), two relatively uncommon cancer types with aggressive clinical behavior. In the first project, we sequenced 10 exomes of USCs and validated the most frequent somatic mutations in 66 additional USCs. In addition, gene copy number was characterized by single-nucleotide polymorphism (SNP) arrays in 23 USCs. Frequent somatic mutations were identified in TP53 (81.6%), PIK3CA (23.7%), FBXW7 (19.7%), and PPP2R1A (18.4%) in USCs. Concordant PIK3CA, PPP2R1A, and TP53 mutation status between USC and the its precursor lesion, serous endometrial intraepithelial carcinoma (SEIC), were recognized in all SEICs examined. DNA copy number analysis revealed frequent genomic amplification of the CCNE1 locus and deletion of the FBXW7 locus. Among 23 uterine serous carcinomas that were subjected to SNP array analysis, seven tumors with FBXW7 mutations did not have CCNE1 amplification, and 13 (57%) tumors had either a molecular genetic alteration in FBXW7 or CCNE1 amplification. Nearly half of these uterine serous carcinomas harbored PIK3CA mutation and/or PIK3CA amplification. This study implicated genetic aberrations of the p53, cyclin E–FBXW7, and PI3K pathways as major mechanisms in the development of USC. In the second project, I evaluated in 525 gynecologic cancers the prevalence of gain-of-function TERT promoter mutations, which have been shown to promote transcriptional activation of TERT and likely play a key role in immortalization of some cancer types. With the exception of ovarian clear cell carcinomas (OCCC), of which 15.9% harbored the mutations, the majority of gynecological malignancies were wild-type. TERT promoter mutation does not appear to be an early event during oncogenesis, as it was not detected in the contiguous endometriosis associated with OCCC. OCCC cell lines with TERT promoter mutations exhibited higher TERT mRNA expression than those with wild-type sequences. TERT promoter mutation tended to be mutually exclusive with loss of ARID1A protein expression and PIK3CA mutation in ovarian clear cell carcinomas. These results suggest that aberrations in telomere biology may play an important role in the pathogenesis of OCCC